Processes for the preparation of pesticidal compounds

ABSTRACT

The present application provides processes for making pesticidal compounds and compounds useful both as pesticides and in the making of pesticidal compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a divisional of U.S. application Ser. No. 14/718,621filed on May 21, 2014, which is a divisional of U.S. application Ser.No. 14/517,595 filed on Oct. 17, 2014, which claims the benefit of thefollowing U.S. Provisional Patent Applications: Ser. No. 62/034,456,filed Aug. 7, 2014; Ser. No. 62/001,925, filed May 22, 2014; and Ser.No. 61/892,124, filed Oct. 17, 2013, the entire disclosures of theseapplications are hereby expressly incorporated by reference into thisApplication.

TECHNICAL FIELD

This application relates to efficient and economical synthetic chemicalprocesses for the preparation of pesticidal thioethers and pesticidalsulfoxides. Further, the present application relates to certain novelcompounds necessary for their synthesis. It would be advantageous toproduce pesticidal thioethers and pesticidal sulfoxides efficiently andin high yield from commercially available starting materials.

DETAILED DESCRIPTION

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

As used herein, the term “alkyl” denotes branched or unbranchedhydrocarbon chains.

As used herein, the term “alkynyl” denotes branched or unbranchedhydrocarbon chains having at least one C≡C.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone is a saturated cyclic hydrocarbon group, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl.

The term “thio” as used herein as part of another group refers to asulfur atom serving as a linker between two groups.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine.

The compounds and process of the present application are described indetail below in scheme 1.

In step a of Scheme 1, 4-nitropyrazole is halogenated and reduced toyield 3-chloro-1H-pyrazol-4-amine hydrochloride (1a). The halogenationoccurs at the 3-carbon through the use of concentrated (37 weightpercent) hydrochloric acid. The reduction occurs with triethylsilane andpalladium on alumina (preferably about 1 to 10 weight percent palladiumon alumina, more preferably about 5 weight percent). This reaction maybe conducted at a temperature from about 10° C. to about 20° C. Thisreaction may be conducted in a polar protic solvent, such as methanol orethanol, preferably ethanol. It was surprisingly discovered, that byutilizing about 1 to about 4 equivalents, preferably, about 2.5equivalents to about 3.5 equivalents of triethylsilane in this step,while conducting the reaction between about 0° C. to about 40° C.,preferably 10° C. and about 20° C., gives about a 10:1 molar ratio ofthe desired halogenated product 3-chloro-1H-pyrazol-4-aminehydrochloride (1a)

versus the undesired product

In step b of Scheme 1,3-chloro-1H-pyrazol-4-amine hydrochloride (1a) isreacted with an activated carbonyl thioether, indicated asX¹C(═O)C₁-C₄-alkyl-S—R¹, to produce pesticidal thioether (3a). R¹ isselected from the group consisting of C₁-C₄-haloalkyl andC₁-C₄-alkyl-C₃-C₆-halocycloalkyl, preferably, R¹ is selected fromCH₂CH₂CF₃ or CH₂(2,2-difluorocyclopropyl). X¹ is selected from Cl,OC(═O)C₁-C₄ alkyl, or a group X¹ that forms an activated carboxylicacid. When X¹ is Cl or OC(═O)C₁-C₄ alkyl, the reaction may be conductedin the presence of a base preferably, sodium bicarbonate at temperaturesfrom about −10° C. to about 40° C. to yield pesticidal thioether (3a).The reaction may be conducted in a solvent mixture such astetrahydrofuran and water. It has been surprisingly discovered thethioether (3a) produced by this synthetic route is only monoacylated dueto the presence of the chloro group at the 3-position of the pyrazolering. Described herein is a comparative example without a halogen at the3-position that yielded the double acylated product (see “CE-1”).Further, comparative example with a bromo group at the 3-positionafforded the product in a surprisingly low yield compared to the yieldwith the chloro group (see “CE-2”).

Alternatively, the reaction may be accomplished whenX¹C(═O)C₁-C₄-alkyl-S—R¹ is an activated carboxylic acid activated bysuch reagents as 2,4,6-tripropyl-trioxatriphosphinane-2,4-trioxide,carbonyldiimidazole, dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide at temperatures from about0° C. to about 80° C.; this reaction may also be facilitated withuronium or phosphonium activating groups such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate, in the presence of an amine base such asdiisopropylethylamine or triethylamine in a polar aprotic solvent suchas N,N-dimethylformamide, tetrahydrofuran, or dichloromethane, attemperatures from about −10° C. to about 30° C. to form pesticidalthioether (3a). Activated carbonyl thioethers, may be prepared fromX¹C(═O)C₁-C₄-alkyl-S—R¹, wherein X¹ is OH, which may be prepared byreacting the corresponding ester thioether, indicated asX¹C(═O)C₁-C₄-alkyl-S—R¹ wherein X¹ is OC₁-C₄-alkyl, with a metalhydroxide such as lithium hydroxide in a polar solvent such as methanolor tetrahydrofuran. Alternatively, X¹C(═O)C₁-C₄-alkyl-S—R¹, wherein X¹is OH or OC₁-C₄-alkyl may be prepared by the photochemical free-radicalcoupling of 3-mercaptopropionic acid and esters thereof with3,3,3-trifluoropropene in the presence of2,2-dimethoxy-2-phenylacetophenone initiator and long wavelength UVlight in an inert organic solvent. While stoichiometric amounts of3-mercaptopropionic acid or esters thereof and 3,3,3-trifluoropropeneare required, because of its low boiling point, excess3,3,3-trifluoropropene is usually employed to compensate for routinelosses. From about 1 to about 10 mole percent initiator,2,2-dimethoxy-2-phenylacetophenone, is typically used, with about 5 molepercent being preferred. Long wavelength UV light is sometimes called“black light” and ranges from about 400 to about 365 nanometers. Thephotochemical coupling is conducted in an inert organic solvent. Typicalinert organic solvents must remain liquid to about −50° C., must remainrelatively inert to the free radical conditions and must dissolve thereactants at reaction temperatures. Preferred inert organic solvents arearomatic and aliphatic hydrocarbons like toluene. The temperature atwhich the reaction is conducted is not critical but usually is fromabout −50° C. to about 35° C. Initially, it is important to keep thetemperature below the boiling point of 3,3,3-trifluoropropene, i.e.,about −18 to about −16° C. In a typical reaction, the inert organicsolvent is cooled to less than about −50° C. and the3,3,3-trifluoropropene is bubbled into the solvent. The3-mercaptopropionic acid or esters thereof and2,2-dimethoxy-2-phenylacetophenone are added and a long wave function(366 nm) UVP lamp (4 watt) is turned on. After sufficient conversion of3-mercapto-propionic acid or esters thereof, the light is turned off andthe solvent removed.

3-((3,3,3-Trifluoropropyl)thio)propanoic acid may also be prepared bythe low temperature free-radical initiated coupling of3-mercaptopropionic acid with 3,3,3-trifluoropropene in the presence of2,2′-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70) initiator attemperatures of about −50° C. to about 40° C. in an inert organicsolvent. While stoichiometric amounts of 3-mercaptopropionic acid and3,3,3-trifluoropropene are required, because of its low boiling point,excess 3,3,3-trifluoropropene is usually employed to compensate forroutine losses. From about 1 to about 10 mole percent initiator, V-70,is typically used, with about 5 mole percent being preferred. The lowtemperature free-radical initiated coupling is conducted in an inertorganic solvent. Typical inert organic solvents must remain liquid toabout −50° C., must remain relatively inert to the free radicalconditions and must dissolve the reactants at reaction temperatures.Preferred inert organic solvents are toluene, ethyl acetate, andmethanol. The temperature at which the reaction is conducted from about−50° C. to about 40° C. The solution is cooled to less than about −50°C. and the 3,3,3-trifluoropropene is transferred into the reactionmixture. After stiffing at room temperature for 24 hours, the reactionmixture is heated to about 50° C. for about 1 hour to decompose anyremaining V-70 initiator followed by cooling and solvent removal.

In step c of Scheme 1, thioether (3a) is reacted with a halopyridine,preferably, 3-bromopyridine in the presence of a copper salt, (such ascopper(I) chloride, copper(II) chloride, and copper(I) iodide), a basesuch as potassium phosphate, and potassium carbonate, preferablypotassium carbonate, and N,N′-dimethylethane-1,2-diamine to yieldpesticidal thioether (3b).

This synthetic method is simpler and reduces the costs of startingmaterials over known heteroarylation methods. The process may beconducted in a polar solvent, such as, acetonitrile, dioxane, orN,N-dimethylformamide at a temperature between about 50° C. and about110° C., preferably between about 70° C. and about 90° C. It ispreferred that the reaction mixture is stirred with heating for between2 hours and 24 hours.

In step d of Scheme 1, pesticidal thioether (3b) is alkylated preferablywith a R²—X² to yield pesticidal thioether (3c), wherein X² is a leavinggroup. The leaving group may be selected from halo, mesylate, ortosylate. R² is selected from C₁-C₄-alkyl, C₂-C₄-alkynyl, preferably,methyl, ethyl, and propargyl. R²—X² may be selected from methyl iodide,ethyl bromide, ethyl iodide, propargyl chloride, propargyl bromide,ethyl mesylate, propargyl mesylate, ethyl tosylate, and propargyltosylate. The alkylation is conducted in the presence of an inorganicbase, preferably, metal carbonates such as cesium carbonate, metalhydroxides, metal phosphates, metal hydrides, conducted in the presenceof a polar solvent, preferably N,N-dimethylformamide at temperaturesfrom about 0° C. to about 80° C.

Alternatively, in step d of Scheme 1, the alkylation of pesticidalthioether (3b) may be conducted in the presence of a base such as sodiumhydride, in the presence of a polar aprotic solvent, such asN,N-dimethylformamide, tetrahydrofuran, hexamethylphosphoramide,dimethylsulfoxide, N-methyl-2-pyrrolidinone, and sulfolane, attemperatures from about 0° C. to about 30° C. It has been unexpectedlydiscovered that the use of sulfolane as solvent promotes the alkylationreaction over the competitive retro-Michael-type elimination of theC₁-C₄-alkyl-S—R¹ unit (see “CE-3”). It has been discovered that thecatalytic use of an iodide additive, such as potassium iodide ortetrabutylammonium iodide decreases the time necessary for the reactionto occur to about 24 hours. It was also discovered that heating thereaction at about 50° C. to about 70° C. in a sealed reactor (to preventloss of ethyl bromide) decreases the reaction time to about 24 hours.

In step e of Scheme 1 thioether (3c) is oxidized with hydrogen peroxide(H₂O₂) in methanol to yield the desired pesticidal sulfoxides (3d).

EXAMPLES

The following examples are presented to better illustrate the processesof the present application.

Example 1 3-chloro-1H-pyrazol-4-amine Hydrochloride (1a)

A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with amechanical stirrer, temperature probe and nitrogen inlet, was chargedwith 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt%, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition ofconcentrated hydrochloric acid (37 wt %, 180 mL). The reaction wascooled to 15° C., and triethylsilane (171 mL, 1072 mmol) was addedslowly via addition funnel over 1 hour, while maintaining the internaltemperature at 15° C. The reaction was stirred at 15° C. for 72 hours,after which the reaction mixture was filtered through a Celite® pad andthe pad was rinsed with warm ethanol (40° C., 2×100 mL). The combinedfiltrates were separated and the aqueous layer (bottom layer) wasconcentrated to ˜100 mL. Acetonitrile (200 mL) was added and theresulting suspension was stirred at 20° C. for 1 hour and filtered. Thefilter cake was rinsed with acetonitrile (2×100 mL) and dried undervacuum at 20° C. to afford a white solid (˜10:1 mixture of 1a and1H-pyrazol-4-amine, 65.5 g, 99%): ¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (bs,3H), 8.03 (s, 1H); EIMS m/z 117 ([M]⁺).

Example 2N-(3-chloro-1H-pyraxol-4-yl)-3-((3,3,3,trifluoropropyl)thio)propanamide(Compound 2.3)

A 100 mL, 3-neck flask was charged with 3-chloro-1H-pyrazol-4-aminehydrochloride (5.00 g, 32.5 mmol), tetrahydrofuran (25 mL) and water (25mL). The resulting suspension was cooled to 5° C. and sodium bicarbonate(10.9 g, 130 mmol) was added, followed by dropwise addition of3-((3,3,3,-trifluoropropyl)thio)propanoyl chloride (7.52 g, 34.1 mmol)at <5° C. The reaction was stirred at <10° C. for 1 hour, at which pointthin layer chromatography analysis (Eluent: 1:1 ethyl acetate/hexane)indicated the starting material was consumed and the desired product wasformed. The reaction mixture was diluted with ethyl acetate (25 mL) andwater (25 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (3×25 mL). The organic layers were combinedand concentrated to dryness. The residue was suspended in 2:1 methyltert-butylether/heptanes (30 mL), stirred for 1 hour and filtered. Thesolid was rinsed with 2:1 methyl tert-butylether/heptanes (20 mL) andfurther dried under vacuum at room temperature (about 22° C.) to afforda white solid (7.80 g, 80%): mp 83-85° C.; ¹H NMR (400 MHz, DMSO-d₆) δ12.90 (s, 1H), 9.59 (s, 1H), 8.02 (s, 1H), 2.82 (t, J=7.2 Hz, 2H),2.76-2.69 (m, 2H), 2.66 (t, J=7.1 Hz, 2H), 2.62-2.48 (m, 2H); ¹³C NMR(101 MHz, DMSO-d₆) δ 168.97, 129.95, 126.60 (q, J=277.4 Hz), 123.42,116.60, 35.23, 33.45 (q, J=27.3 Hz), 26.85, 23.03 (q, J=3.4 Hz); EIMSm/z 301 ([M]⁺).

Example 3 3-((3,3,3-trifluoropropyl)thio)propanoic Acid

A 100 mL, 3-neck round bottom flask was charged with 3-bromopropanoicacid (500 mg, 3.27 mmol) and methanol (10 mL), potassium hydroxide (403mg, 7.19 mmol) was added, followed by 3,3,3-trifluoropropane-1-thiol(468 mg, 3.60 mmol). The mixture was heated at 50° C. for 4 hours, afterwhich it was acidified with 2 N hydrochloric acid and extracted withmethyl tert-butylether (2×10 mL). The organic layer was concentrated todryness to afford a light yellow oil (580 mg, 88%): ¹H NMR (400 MHz,CDCl₃) δ 2.83 (td, J=7.1, 0.9 Hz, 2H), 2.78-2.64 (m, 4H), 2.48-2.32 (m,2H).

Alternate Synthetic Route to 3-((3,3,3-trifluoropropyl)thio)propanoicAcid: A 100 mL stainless steel Parr reactor was charged withazobisisobutyronitrile (0.231 g, 1.41 mmol), toluene (45 mL),3-mercaptopropionic acid (3.40 g, 32.0 mmol), and octanophenone (526.2mg) as an internal standard and was purged and pressure checked withnitrogen. The reactor was cooled with dry ice and the3,3,3-trifluoropropene (3.1 g, 32.3 mmol) was condensed into thereactor. The ice bath was removed and the reactor heated to 60° C. andstirred for 27 hours. The internal yield of the reaction was determinedto be 80% by use of the octanophenone internal standard. The pressurewas released and the crude mixture removed from the reactor. The mixturewas concentrated by rotary evaporation and 50 mL of 10% sodium hydroxidewas added. The solution was washed with methyl tert-butylether (50 mL)then acidified to pH ˜1 with 6 N hydrochloric acid. The product wasextracted with 100 mL methyl tert-butylether, dried over magnesiumsulfate, filtered, and concentrated to give the crude titled compound asan oil (5.34 g, 26.4 mmol, 83%, 87.5 area % on GC): ¹H NMR (400 MHz,CDCl₃) δ 2.83 (td, J=7.1, 0.9 Hz, 2H), 2.76-2.64 (m, 4H), 2.47-2.30 (m,2H); ¹³C NMR (101 MHz, CDCl₃) δ 177.68, 125.91 (q, J=277.1 Hz), 34.58(q, J=28.8 Hz), 34.39, 26.63, 24.09 (q, J=3.3 Hz); ¹⁹F NMR (376 MHz,CDCl₃) δ −66.49.

Alternate Synthetic Route to 3-((3,3,3-trifluoropropyl)thio)propanoicAcid: A 250 mL three-neck round bottomed flask was charged with toluene(81 mL) and cooled to <−50° C. with a dry ice/acetone bath.3,3,3-Trifluoropropene (10.28 g, 107.0 mmol) was bubbled into thesolvent and the ice bath was removed. 3-Mercaptopropionic acid (9.200 g,86.70 mmol) and 2,2-dimethoxy-2-phenylacetophenone (1.070 g, 4.170 mmol)were added and the long wave light (366 nm, 4 watt UVP lamp) was turnedon (Starting temperature: −24° C.). The reaction reached a temperatureof 27.5° C. due to heat from the lamp. The reaction was stirred underthe black light on for 4 hours. After 4 hours the black light was turnedoff and the reaction concentrated by rotary evaporation (41° C., 6 mmHg) giving a pale yellow oil (18.09 g, 51:1 linear:branched isomer, 90wt % linear isomer by GC internal standard assay, 16.26 g active, 93%).The crude material was dissolved in 10% sodium hydroxide w/w (37.35 g)and was washed with toluene (30 mL) to remove non-polar impurities. Theaqueous layer was acidified to pH ˜2-3 with hydrochloric acid (2 N,47.81 g) and was extracted with toluene (50 mL). The organic layer waswashed with water (40 mL) and dried over magnesium sulfate, filtered,and concentrated by rotary evaporation giving a pale yellow oil (14.15g, 34:1 linear:branched isomer, 94 wt % linear isomer by GC internalstandard assay, 13.26 g active, 76%).

Alternative Synthesis of 3-((3,3,3-trifluoropropyl)thio)propanoic Acid:A 100 mL stainless steel Parr reactor was charged with3-mercaptopropionic acid (3.67 g, 34.6 mmol), toluene (30.26 g), and2,2′-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70, 0.543 g, 1.76mmol) and the reactor was cooled with a dry ice/acetone bath, purgedwith nitrogen, and pressure checked. 3,3,3-Trifluoropropene (3.20 g,33.3 mmol) was added via transfer cylinder and the reaction was allowedto warm to 20° C. After 24 hours, the reaction was heated to 50° C. for1 hour to decompose any remaining V-70 initiator. The reaction wasallowed to cool to room temperature. The solution was concentrated byrotary evaporation to provide the title compound (6.80 g, 77.5 wt %linear isomer by GC internal standard assay, 5.27 g active, 76%, 200:1linear:branched by GC, 40:1 linear:branched by fluorine NMR)

Example 4 methyl-3-((3,3,3-trifluoropropyl)thio)propionate (Compound7.1)

A 100 mL stainless steel Pan reactor was charged withazobisisobutyronitrile (0.465 g, 2.83 mmol), toluene (60 mL) andmethyl-3-mercaptopropionate (7.40 g, 61.6 mmol) and was purged andpressure checked with nitrogen. The reactor was cooled with dry ice andthe 3,3,3-trifluopropopene (5.70 g, 59.3 mmol) was condensed into thereactor. The ice bath was removed and the reactor heated to 60° C. andstirred to 24 hours. The heat was turned off and the reaction left atroom temperature overnight. The mixture was removed from the reactor andconcentrated to a yellow liquid. The liquid was distilled by vacuumdistillation (2 Torr, 85° C.) and three fractions were collected:fraction 1 (1.3 g, 6.01 mmol, 10%, 70.9 area % by GC), fraction 2 (3.7g, 17.1 mmol, 29%, 87 area % by GC), and fraction 3 (4.9 g, 22.7 mmol,38%, 90.6 area % by GC): ¹H NMR (400 MHz, CDCl₃) δ 3.71 (s, 3H), 2.82,(td, J=7.3, 0.7 Hz, 2H), 2.75-2.68 (m, 2H), 2.63 (td, J=7.2, 0.6 Hz,2H), 2.47-2.31 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 172.04, 125.93 (q,J=277.2 Hz), 51.86, 34.68 (q, J=28.6 Hz), 34.39, 27.06, 24.11 (q, J=3.3Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −66.53.

Alternate Synthetic Route tomethyl-3-((3,3,3-trifluoropropyl)thio)propionate: A 500 mL three-neckround bottomed flask was charged with toluene (200 mL) and cooled to<−50° C. with a dry ice/acetone bath. 3,3,3-Trifluoropropene (21.8 g,227 mmol) was condensed into the reaction by bubbling the gas throughthe cooled solvent and the ice bath was removed. Methyl3-mercaptopropionate (26.8 g, 223 mmol) and2,2-dimethoxy-2-phenylacetophenone (2.72 g, 10.61 mmol) were added and aUVP lamp (4 watt) that was placed within 2 centimeters of the glass wallwas turned on to the long wave function (366 nanometers). The reactionreached 35° C. due to heat from the lamp. After 4 hours, all of thetrifluoropropene was either consumed or boiled out of the reaction. Thelight was turned off and the reaction stirred at room temperatureovernight. After 22 hours, more trifluoropropene (3.1 g) was bubbledthrough the mixture at room temperature and the light was turned on foran additional 2 hours. The reaction had converted 93% so no moretrifluoropropene was added. The light was turned off and the mixtureconcentrated on the rotovap (40° C., 20 torr) giving a yellow liquid(45.7 g, 21.3:1 linear: branched isomer, 75 wt % pure linear isomerdetermined by a GC internal standard assay, 34.3 g active, 71% in potyield).

Alternate Synthetic Route tomethyl-3-((3,3,3-trifluoropropyl)thio)propionate: A 100 mL stainlesssteel Parr reactor was charged with methyl 3-mercaptopropionate (4.15 g,34.5 mmol), toluene (30.3 g), and 2,2′-azobis(4-methoxy-2,4-dimethyl)valeronitrile (V-70, 0.531 g, 1.72 mmol) and the reactor was cooled witha dry ice/acetone bath, purged with nitrogen, and pressure checked.3,3,3-Trifluoropropene (3.40 g, 35.4 mmol) was added via transfercylinder and the reaction was allowed to warm to 20° C. After 23 hoursthe reaction was heated to 50° C. for 1 hour to decompose any remainingV-70 initiator. The reaction was allowed to cool to room temperature.The solution was concentrated to provide the title compound (7.01 g,66%, 70.3 wt % linear isomer by GC internal standard assay, 4.93 gactive, 66%, 24:1 linear:branched by GC, 18:1 linear:branched byfluorine NMR).

Example 5N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 5.3)

A 100 mL, 3-neck round bottom flask was charged with copper(I) iodide(0.343 g, 1.80 mmol), acetonitrile (50 mL),N,N′-dimethylethane-1,2-diamine (0.318 g, 3.61 mmol),N-(3-chloro-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(2.72 g, 9.02 mmol), K₂CO₃ (2.49 g, 18.0 mmol) and 3-bromopyridine (1.71g, 10.8 mmol). The mixture was purged with nitrogen three times andheated to 80° C. for 4 hours, at which point thin layer chromatographyanalysis (Eluent: ethyl acetate) indicated that only a trace of startingmaterial remained. The mixture was filtered through a Celite® pad andthe pad was rinsed with acetonitrile (20 mL). The filtrates wereconcentrated to dryness and the residue was purified by flash columnchromatography using 0-100% ethyl acetate/hexanes as eluent. Thefractions containing pure product were concentrated to dryness andfurther dried under vacuum to afford a white solid (1.82 g, 53%): mp99-102° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (s, 1H), 9.05 (d, J=2.7 Hz,1H), 8.86 (s, 1H), 8.54 (dd, J=4.5, 1.4 Hz, 1H), 8.21 (ddd, J=8.4, 2.7,1.4 Hz, 1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 2.86 (t, J=7.3 Hz, 2H), 2.74(td, J=6.5, 5.6, 4.2 Hz, 4H), 2.59 (ddd, J=11.7, 9.7, 7.4 Hz, 2H); ¹³CNMR (101 MHz, DMSO-d₆) δ 169.32, 147.49, 139.44, 135.47, 133.40, 126.60(q, J=296 Hz), 125.49, 124.23, 122.30, 120.00, 35.18, 33.42 (q, J=27.2Hz), 26.77, 23.05 (q, J=3.3 Hz); EIMS m/z 378 ([M]⁺).

Example 6N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 6.3)

A 100 mL, 3-neck round bottom flask, equipped with mechanical stirrer,temperature probe and nitrogen inlet was charged with cesium carbonate(654 mg, 2.01 mmol),N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(380 mg, 1.00 mmol) and N,N-dimethylformamide, (5 mL). Iodoethane(0.0890 mL, 1.10 mmol) was added dropwise. The reaction was stirred at40° C. for 2 hours, at which point thin layer chromatography analysis(Eluent: ethyl acetate) indicated that only a trace of starting materialremained. The reaction mixture was cooled to 20° C. and water (20 mL)was added. It was extracted with ethyl acetate (2×20 mL) and thecombined organic layers were concentrated to dryness at <40° C. Theresidue was purified by flash column chromatography using 0-100% ethylacetate/hexane as eluent. The fractions containing pure product wereconcentrated to dryness to afford a colorless oil (270 mg, 66%): ¹H NMR(400 MHz, DMSO-d₆) δ 9.11 (d, J=2.7 Hz, 1H), 8.97 (s, 1H), 8.60 (dd,J=4.8, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.60 (ddd,J=8.4, 4.7, 0.8 Hz, 1H), 3.62 (q, J=7.1 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H),2.66-2.57 (m, 2H), 2.57-2.44 (m, 2H), 2.41 (t, J=7.0 Hz, 2H), 1.08 (t,J=7.1 Hz, 3H); EIMS: m/z 406 ([M]⁺).

Alternate Synthetic Route toN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 6.3): To 3-neck round bottomed flask (50 mL) was added sodiumhydride (60% in oil, 0.130 g, 3.28 mmol) and sulfolane (16 mL). The graysuspension was stirred for 5 minutes thenN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(1.20 g, 3.16 mmol) dissolved in sulfolane (25 mL) was slowly addeddropwise over 5 minutes. The mixture became a light gray suspensionafter 3 minutes and was allowed to stir for 5 minutes after which timeethyl bromide (0.800 mL, 10.7 mmol) and potassium iodide (0.120 g, 0.720mmol) were added sequentially. The cloudy suspension was then allowed tostir at room temperature. The reaction was quenched after 6 hours bybeing poured drop-wise into cooled ammonium formate/acetonitrilesolution (30 mL). The resulting orange colored solution was stirred andtetrahydrofuran (40 mL) was added. The mixture was assayed, usingoctanophenone as a standard, and found to contain 1.09 g (85%) of thedesired product with a selectivity versus the retro-Michael-likedecomposition product of 97:3.

Example 7N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)sulfoxo)propanamide(Compound 7.3)

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(57.4 g, 141 mmol) was stirred in methanol (180 mL). To the resultingsolution was added hydrogen peroxide (43.2 mL, 423 mmol) dropwise usinga syringe. The solution was stirred at room temperature for 6 hours, atwhich point LCMS analysis indicated that the starting material wasconsumed. The mixture was poured into dichloromethane (360 mL) andwashed with aqueous sodium carbonate. The organic layer was dried oversodium sulfate and concentrated to provide a thick yellow oil. The crudeproduct was purified by flash column chromatography using 0-10%methanol/ethyl acetate as eluent and the pure fractions were combinedand concentrated to afford the desired product as an oil (42.6 g, 68%):¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (dd, J=2.8, 0.7 Hz, 1H), 8.98 (s, 1H),8.60 (dd, J=4.7, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.60(ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.61 (q, J=7.4, 7.0 Hz, 2H), 3.20-2.97(m, 2H), 2.95-2.78 (m, 2H), 2.76-2.57 (m, 2H), 2.58-2.45 (m, 2H), 1.09(t, J=7.1 Hz, 3H); ESIMS m/z 423 ([M+H]⁺).

Example 8 3-((3,3,3-trifluoropropyl)thio)propanoyl Chloride

A dry 5 L round bottom flask equipped with magnetic stirrer, nitrogeninlet, reflux condenser, and thermometer, was charged with3-((3,3,3-trifluoropropyl)thio)propanoic acid (188 g, 883 mmol) indichloromethane (3 L). Thionyl chloride (525 g, 321 mL, 4.42 mol) wasthen added dropwise over 50 minutes. The reaction mixture was heated toreflux (about 36° C.) for 2 hours, then cooled to room temperature.Concentration under vacuum on a rotary evaporator, followed bydistillation (40 Torr, product collected from 123-127° C.) gave thetitle compound as a clear colorless liquid (177.3 g, 86%): ¹H NMR (400MHz, CDCl₃) δ 3.20 (t, J=7.1 Hz, 2H), 2.86 (t, J=7.1 Hz, 2H), 2.78-2.67(m, 2H), 2.48-2.31 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −66.42, −66.43,−66.44, −66.44.

Example 9 3-(((2,2-difluorocyclopropyl)methyl)thio)propanoic acid

Powdered potassium hydroxide (423 mg, 7.54 mmol) and2-(bromomethyl)-1,1-difluorocyclopropane (657 mg, 3.84 mmol) weresequentially added to a stirred solution of 3-mercaptopropanoic acid(400 mg, 3.77 mmol) in methanol (2 mL) at room temperature. Theresulting white suspension was stirred at 65° C. for 3 hours andquenched with 1 N aqueous hydrochloric acid and diluted with ethylacetate. The organic phase was separated and the aqueous phase extractedwith ethyl acetate (2×50 mL). The combined organic extracts were driedover magnesium sulfate, filtered and concentrated in vacuo to give thetitle molecule as a colorless oil (652 mg, 84%): IR (KBr thin film)3025, 2927, 2665, 2569, 1696 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 2.85 (t,J=7.0 Hz, 2H), 2.82-2.56 (m, 4H), 1.88-1.72 (m, 1H), 1.53 (dddd, J=12.3,11.2, 7.8, 4.5 Hz, 1H), 1.09 (dtd, J=13.1, 7.6, 3.7 Hz, 1H); ESIMS m/z195.1 ([M−H]⁻).

Example 10 3-(((2,2-difluorocyclopropyl)methyl)thio)propanoyl chloride

In a 3 L 3-neck round bottomed-flask equipped with an overhead stirrer,a temperature probe, and addition funnel and an nitrogen inlet wascharged with 3-(((2,2-difluorocyclopropyl)methyl)thio)propanoic acid(90.0 g, 459 mmol) that was immediately taken up in dichloromethane (140mL) with stirring. At room temperature, thionyl chloride (170 mL, 2293mmol) in dichloromethane (100 mL) was added drop-wise with stirring. Thereaction mixture was heated to 40° C. and heated for 2 hours. Thereaction was determined to be complete by ¹H NMR (An aliquot of thereaction mixture was taken, and concentrated down via rotaryevaporator). The reaction was allowed to cool to room temperature andthe mixture was transferred to a dry 3 L round bottomed flask andconcentrated via the rotary evaporator. This resulted in honey-coloredoil (95 g). The contents were gravity filtered through paper and thepaper rinsed with diethyl ether (10 mL). The rinse was added to theflask. This gave a clear yellow liquid. The liquid was placed on arotary evaporator to remove the ether. This gave a yellow oil (92.4 g).The oil was Kugelrohr distilled (bp 100-110° C./0.8-0.9 mm Hg) toprovide the title compound as a colorless oil (81.4 g, 81%): ¹H NMR (400MHz, CDCl₃) δ 3.27-3.12 (m, 2H), 2.89 (t, J=7.1 Hz, 2H), 2.67 (ddd,J=6.8, 2.6, 1.0 Hz, 2H), 1.78 (ddq, J=13.0, 11.3, 7.4 Hz, 1H), 1.64-1.46(m, 1H), 1.09 (dtd, J=13.2, 7.7, 3.7 Hz, 1H).

Biological Examples Example A Bioassays on Green Peach Aphid (“GPA”)(Myzus persicae) (MYZUPE

GPA is the most significant aphid pest of peach trees, causing decreasedgrowth, shriveling of leaves, and the death of various tissues. It isalso hazardous because it acts as a vector for the transport of plantviruses, such as potato virus Y and potato leafroll virus to members ofthe nightshade/potato family Solanaceae, and various mosaic viruses tomany other food crops. GPA attacks such plants as broccoli, burdock,cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce,macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress andzucchini among other plants. GPA also attacks many ornamental crops suchas carnations, chrysanthemum, flowering white cabbage, poinsettia androses. GPA has developed resistance to many pesticides.

Several molecules disclosed herein were tested against GPA usingprocedures described below.

Cabbage seedling grown in 3-in pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-5-GPA (wingless adult and nymph stages) one day prior to chemicalapplication. Four pots with individual seedlings were used for eachtreatment. Test compounds (2 mg) were dissolved in 2 mL of acetone/MeOH(1:1) solvent, forming stock solutions of 1000 ppm test compound. Thestock solutions were diluted 5× with 0.025% Tween 20 in water to obtainthe solution at 200 ppm test compound. A hand-held aspirator-typesprayer was used for spraying a solution to both sides of the cabbageleaves until runoff. Reference plants (solvent check) were sprayed withthe diluent only containing 20% by volume acetone/MeOH (1:1) solvent.Treated plants were held in a holding room for three days atapproximately 25° C. and ambient relative humidity (RH) prior tograding. Evaluation was conducted by counting the number of live aphidsper plant under a microscope. Percent Control was measured by usingAbbott's correction formula (W. S. Abbott, “A Method of Computing theEffectiveness of an Insecticide” J. Econ. Entomol 18 (1925), pp.265-267) as follows.Corrected % Control=100*(X−Y)/X

-   -   where    -   X=No. of live aphids on solvent check plants and        -   Y=No. of live aphids on treated plants

The results are indicated in the table entitled “Table 1: GPA (MYZUPE)and sweetpotato whitefly-crawler (BEMITA) Rating Table”.

Example B Bioassays on Sweetpotato Whitefly Crawler (Bemisia tabaci)(BEMITA.)

The sweetpotato whitefly, Bemisia tabaci (Gennadius), has been recordedin the United States since the late 1800s. In 1986 in Florida, Bemisiatabaci became an extreme economic pest. Whiteflies usually feed on thelower surface of their host plant leaves. From the egg hatches a minutecrawler stage that moves about the leaf until it inserts itsmicroscopic, threadlike mouthparts to feed by sucking sap from thephloem. Adults and nymphs excrete honeydew (largely plant sugars fromfeeding on phloem), a sticky, viscous liquid in which dark sooty moldsgrow. Heavy infestations of adults and their progeny can cause seedlingdeath, or reduction in vigor and yield of older plants, due simply tosap removal. The honeydew can stick cotton lint together, making it moredifficult to gin and therefore reducing its value. Sooty mold grows onhoneydew-covered substrates, obscuring the leaf and reducingphotosynthesis, and reducing fruit quality grade. It transmittedplant-pathogenic viruses that had never affected cultivated crops andinduced plant physiological disorders, such as tomato irregular ripeningand squash silverleaf disorder. Whiteflies are resistant to manyformerly effective insecticides.

Cotton plants grown in 3-inch pots, with 1 small (3-5 cm) true leaf,were used at test substrate. The plants were placed in a room withwhitely adults. Adults were allowed to deposit eggs for 2-3 days. Aftera 2-3 day egg-laying period, plants were taken from the adult whiteflyroom. Adults were blown off leaves using a hand-held Devilbliss sprayer(23 psi). Plants with egg infestation (100-300 eggs per plant) wereplaced in a holding room for 5-6 days at 82° F. and 50% RH for egg hatchand crawler stage to develop. Four cotton plants were used for eachtreatment. Compounds (2 mg) were dissolved in 1 mL of acetone solvent,forming stock solutions of 2000 ppm. The stock solutions were diluted10× with 0.025% Tween 20 in water to obtain a test solution at 200 ppm.A hand-held Devilbliss sprayer was used for spraying a solution to bothsides of cotton leaf until runoff. Reference plants (solvent check) weresprayed with the diluent only. Treated plants were held in a holdingroom for 8-9 days at approximately 82° F. and 50% RH prior to grading.Evaluation was conducted by counting the number of live nymphs per plantunder a microscope. Insecticidal activity was measured by using Abbott'scorrection formula (see above) and presented in Table 1.

TABLE 1 GPA (MYZUPE) and sweetpotato whitefly- crawler (BEMITA) RatingTable Example Compound BEMITA MYZUPE 1a B B Compound 2.3 B B Compound5.3 B A Compound 6.3 A A Compound 7.3 A A

% Control of Mortality Rating 80-100 A More than 0-Less than 80 B NotTested C No activity noticed in this bioassay D

Comparative Examples Example CE-1 N-(1-Acetyl-1H-pyrazol-4-yl)acetamide

A 250-mL 3-neck flask was charged with 1H-pyrazol-4-amine (5 g, 60.2mmol) and dichloromethane (50 mL). The resulting suspension was cooledto 5° C. and triethylamine (9.13 g, 90.0 mmol) was added, followed byacetic anhydride (7.37 g, 72.2 mmol) at <20° C. The reaction was stirredat room temperature for 18 hours, at which point thin layerchromatography (Eluent: ethyl acetate) analysis indicated that thereaction was incomplete. Additional triethylamine (4.57 g, 45.0 mmol)and acetic anhydride (3.70 g, 36.0 mmol) were added and the reaction washeated at 30° C. for an additional 3 hours to give a dark solution, atwhich point thin layer chromatography analysis indicated that only atrace of starting material remained. The reaction mixture was purifiedby flash column chromatography using ethyl acetate as eluent. Thefractions containing pure product were combined and concentrated todryness to afford an off-white solid. The solid was dried under vacuumat room temperature for 18 hours (5.55 g, 55%): ¹H NMR (400 MHz,DMSO-d₆) δ 10.30 (s, 1H), 8.39 (d, J=0.7 Hz, 1H), 7.83 (d, J=0.7 Hz,1H), 2.60 (s, 3H), 2.03 (s, 3H); EIMS m/z 167 ([M]⁺).

Example CE-2 N-(3-Bromo-1H-pyrazol-4-yl)acetamide

A 250 mL 3-neck round bottom flask was charged with1H-pyraz-4-amine.hydrobromide (4.00 g, 24.7 mmol) and water (23 mL). Tothe mixture, sodium bicarbonate (8.30 g, 99.0 mmol) was added slowlyover 10 minutes, followed by tetrahydrofuran (23 mL). The mixture wascooled to 5° C. and acetic anhydride (2.60 g, 25.4 mmol) was added over30 minutes while maintaining the internal temperature at <10° C. Thereaction mixture was stirred at ˜5° C. for 20 minutes, at which point ¹HNMR and UPLC analyses indicated that the starting material was consumedand the desired product as well as bis-acetylated byproduct were formed.The reaction was extracted with ethyl acetate and the organic layerswere dried over magnesium sulfate and concentrated. The crude mixturewas triturated with methyl tert-butylether to remove the bisacetylatedproduct to afford ˜1.24 g of a white solid. ¹H NMR analysis showed itwas 1:1.1 desired to undesired bisacetylated product. The solid waspurified by flash column chromatography using 50-100% ethylacetate/hexanes as eluent to afford the desired product as a white solid(380 mg, 7.5%) and the bisacetylated product as a white solid (˜800 mg):¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 9.36 (s, 1H), 7.92 (s, 1H),2.03 (s, 3H); ¹³C NMR (101 MHz, DMSO) δ 167.94, 123.93, 119.19, 119.11,22.63; ESIMS m/z 204 ([M+H]⁺).

Example CE-3 Alkylation Versus Retro-Michael-Like Decomposition

A suspension of sodium hydride (60% in oil, 1.03 eq) and solvent (1 vol)was stirred for 5 minutes.N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)-propanamide(1 eq) dissolved in solvent (2 vol) was slowly added dropwise over 5minutes. Ethyl bromide (3.3 eq) and additive (0.22 eq) were addedsequentially. The suspension was then allowed to stir at roomtemperature until consumption of starting material was observed. Theselectivity of Compound 6.3 over the decomposition product wasdetermined by HPLC (See Table 2).

TABLE 2 Compound Time 6.3:Decomposition Entry Additive Solvent (hours)Product 1 tetrabutyl- N,N- 24  81:19 ammonium dimethylformamide iodide 2potassium N,N- 72 94:6 iodide dimethylformamide 3 potassium N-methyl- 2092:8 iodide pyrolidinone

It should be understood that while this invention has been describedherein in terms of specific embodiments set forth in detail, suchembodiments are presented by way of illustration of the generalprinciples of the invention, and the invention is not necessarilylimited thereto. Certain modifications and variations in any givenmaterial, process step or chemical formula will be readily apparent tothose skilled in the art without departing from the true spirit andscope of the present invention, and all such modifications andvariations should be considered within the scope of the claims thatfollow.

What is claimed is:
 1. A process for the preparation of pesticidalthioethers (3b) useful in the preparation of pesticidal thioethers (3c)and pesticidal sulfoxides (3d),

wherein R¹ is selected form the group consisting of C₁-C₄ haloalkyl andC₁-C₄ alkyl-C₃-C₆ halocycloalkyl which comprises heteroarylation ofthioether (3a)

with a halopyridine in the presence of a copper salt, an amine, and abase.
 2. The process of claim 1, wherein the halopyridine is3-bromopyridine.
 3. The process of claim 1, wherein the copper salt isselected from the group consisting of copper(I) chloride, copper(II)chloride, and copper(I) iodide.
 4. The process of claim 2, wherein thecopper salt is selected from the group consisting of copper(I) chloride,copper(II) chloride, and copper(I) iodide.
 5. The process of claim 1,wherein the base is potassium phosphate or potassium carbonate.
 6. Theprocess of claim 4, wherein the base is potassium phosphate or potassiumcarbonate.
 7. The process of claim 1, wherein the amine isN,N′-dimethylethane-1,2-diamine.
 8. The process of claim 6, wherein theamine is N,N′-dimethylethane-1,2-diamine.
 9. The process of claim 1,wherein the heteroarylation is carried out in a polar solvent.
 10. Theprocess of claim 9, wherein the polar solvent is acetonitrile, dioxaneor N,N-dimethylformamide.
 11. The process of claim 8, wherein theheteroarylation is carried out in a polar solvent.
 12. The process ofclaim 11, wherein the polar solvent is acetonitrile, dioxane orNN-dimethylformamide.
 13. The process of claim 1, wherein theheteroarylation is carried out at a temperature between about 50° C. andabout 110° C.
 14. The process of claim 12, wherein the heteroarylationis carried out at a temperature between about 50° C. and about 110° C.15. The process of claim 1, wherein the R¹ is C₁-C₄ haloalkyl.
 16. Theprocess of claim 15, wherein C₁-C₄ haloalkyl is 3,3,3-trifluoropropyl.17. The process of claim 14, wherein R¹ is C₁-C₄ haloalkyl.
 18. Theprocess of claim 17, wherein C₁-C₄ haloalkyl is 3,3,3-trifluoropropyl.19. The process of claim 1, wherein C₁-C₄ alkyl is ethyl.
 20. Theprocess of claim 18, wherein C₁-C₄ alkyl is ethyl.